The biochemical basis of microRNA targeting efficacy

2019/12/05 by Sean E. McGeary, Kathy S. Lin, Charlie Y. Shi +5 · 39 citations
Biochemistry, Genetics and Molecular Biology · #MicroRNA in disease regulation #RNA Research and Splicing #RNA modifications and cancer

paper · doi:10.1126/science.aav1741

Abstract

MicroRNAs (miRNAs) act within Argonaute proteins to guide repression of messenger RNA targets. Although various approaches have provided insight into target recognition, the sparsity of miRNA-target affinity measurements has limited understanding and prediction of targeting efficacy. Here, we adapted RNA bind-n-seq to enable measurement of relative binding affinities between Argonaute-miRNA complexes and all sequences ≤12 nucleotides in length. This approach revealed noncanonical target sites specific to each miRNA, miRNA-specific differences in canonical target-site affinities, and a 100-fold impact of dinucleotides flanking each site. These data enabled construction of a biochemical model of miRNA-mediated repression, which was extended to all miRNA sequences using a convolutional neural network. This model substantially improved prediction of cellular repression, thereby providing a biochemical basis for quantitatively integrating miRNAs into gene-regulatory networks.

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